As this committee knows well, despite apparently large differences between the more traditional COX-1 inhibiting NSAIDs as far as the occurrence of perforations, ulcers and gastrointestinal bleeding (see attached chart which was included in a December 1994 petition concerning feldene), the committee and the FDA decided on identical class labeling for all of these older NSAIDs which warns about these serious and not infrequent adverse effects.

When the approval of celecoxib and rofecoxib were being considered, we stated that there needed to be clear evidence from comparative long-term, higher dose randomized trials in which celecoxib, rofecoxib or any other COX-2 type of anti-inflammatory drug is compared to the least dangerous of these older drugs, to find out if there is a statistically significantly lower amount of serious GI complications such as perforations, ulcers or bleeding with the COX-2 inhibitor drug. Unless this evidence is produced, there is no more reason, according to the long-standing logic of this committee, to spare any COX-2 inhibitor from the class label now applied to all of the other NSAIDs than there is to distinguish between the members of this older, COX-1-predominant class.

Now that somewhat more definitive studies comparing the risks of serious gastrointestinal complications of celecoxib and rofecoxib with other NSAIDS have been done, the evidence of a statistically significant reduction in these serious complications in people using the two COX-2 inhibitors is still lacking. We agree with the conclusions of FDA Medical Officer Dr. James Whitter's review which found that “Celecoxib did not demonstrate statistical superiority to NSAIDs (pooled) or with the comparator (diclofencac and ibuprofen) with regards to the primary safety endpoint of CSUGIEs (clinically significant upper gastrointestinal events) at any point in the trial although there were trends that favored celecoxib. We also agree with the conclusions of FDA's Office of Postmarketing Drug Risk Assessment that the 73 deaths seen with celecoxib (36) or rofecoxib (37) from gastrointestinal bleeding, obstruction, perforation or stenosis show that the current labeling for the two drugs “reflect[s] the risk of fatal gastrointestinal bleeding, obstruction, perforation or stenosis”.

Not frequently discussed is the fact that the COX-2 enzyme may have other important physiological functions in addition to its role in inflammation. These include GI tract tissue repair (the inhibition of which may explain the serious GI toxicity seen with the drugs), epithelial integrity, cardiac repair after injury, renal vascular homeostasis, fetal renal development during pregnancy, ovarian function and fertility, and cartilage repair. New classes of drugs such as celecoxib and rofecoxib offer not only new mechanisms of action, but also, by virtue of their inhibition of the important COX-2 enzyme, new mechanisms of potential toxicity and the possibility of a new spectrum of adverse effects.

Failure of Protection From Heart Attacks and Probable Cardiac Toxicity

In an editorial accompanying the publication of the CLASS celecoxib study last fall, the authors expressed concern about the theoretical possibility of heart damage by COX-2 inhibitors such as celecoxib and rofecoxib. They stated that “they might increase the risk for thromboembolic cardiovascular events because of the preferential inhibition of endothelial prostacyclin synthesis without corresponding inhibition of platelet thromboxane synthesis.” The editorialists stated, however, that they “did not believe that the trial [as published] showed evidence of this actually occurring.[1]

In a recent study published in the Proceedings of the National Academy of Sciences, the ability of rabbits to withstand temporary experimental coronary artery occlusion was significantly impaired by treatment with either celecoxib or NS-398 which completely blocked the cardioprotective effects of the COX-2 enzyme. The authors of that study concluded that COX-2 enzyme is a “cardioprotective protein”, “plays an essential role in cardioprotection afforded by late phase preconditioning” and found that its inhibition in these circumstances was harmful, resulting in larger myocardial infarctions in the experimental setting. The authors described late-phase preconditioning as “an adaptive response of the heart to a mild ischemic stress that confers relative resistance to a subsequent ischemic insult occurring 12 to 721 hours later.” [2]

In the careful review of the data from the CLASS study, some, but not much of which was published in the JAMA article, FDA Cardio-Renal division reviewer Dr. Throckmorton found that “the incidence of adverse events related to cardiac ischemia (decreased blood flow to the heart) was higher in the celecoxib group ….and was most pronounced in the group of patients not taking ASA (aspirin)” as a cardiovascular protective drug. In these patients the rate of myocardial infarction was also highest in the celecoxib group (0.2%) compared with users of the other two drugs (0.1%). For all patients, on and off aspirin, there was a higher incidence of atrial fibrillation, a cardiac arrhythmia, in the celecoxib group than in either of the other two groups, again more pronounced in the group not taking aspirin. The author concluded by stating that “the data do not exclude a less apparent pro-thrombotic [blood clot forming] effect of celecoxib, reflected in the relative rates of cardiac adverse events related to ischemia.”[3]

These apparent differences in cardiac toxicity, seen in CLASS in which neither of the two comparator drugs is particularly effective, compared to aspirin, in decreasing the occurrence of heart attacks, were magnified in the rofecoxib/naproxen (VIGOR) study by the fact that naproxen, compared to either ibuprofen or diclofenac, does have a coronary protective effect similar to that of aspirin. In the discussion of the rofecoxib study, explaining the difference between naproxen and drugs such as ibuprofen and diclofenac, the authors pointed out that these latter drugs, unlike naproxen, “do not produce sustained, maximal inhibition of platelet aggregation.” [4]

In that study, there was a highly statistically significant increase in heart attacks in the overall rofecoxib group (0.4%) compared to the naproxen group (0.1%). This amounted to approximately 16 heart attacks with rofecoxib (out of 4047 patients) compared with 4 with naproxen (out of 4029 patients).

Recommendations

Once again, a seemingly magic bullet appears to have self-destructed as research reveals the larger context in which it operates--the risks as well as the benefits. The benefits of COX-2 inhibitors as far as reducing GI toxicity appear to have been grossly exaggerated and oversold. Years after the research on these benefits was done, a rapid accumulation of evidence on risks is occurring. For an important enzyme which is close to ubiquitous in the body, it is less than surprising that blocking its activity in one part, the gastrointestinal tract, must be balanced against the apparently harmful effects of blocking its critical functions in other parts of the body.

1. We strongly urge the retention of the NSAID class-warning label for these drugs, possibly adding that there is no evidence of statistically significant reduction in serious GI toxicity for celecoxib. This should take the form of a box warning (for all the drugs) which should be placed at the beginning of the label.

2. A second box warning about cardiovascular toxicity needs to be added. It should warn of the lack of platelet aggregation inhibition of the drugs which protects those at risk from an increased occurrence of heart attacks. In addition, the evidence which is rapidly accumulating about the heart damage caused by these drugs must be mentioned in this cardiovascular box warning. We urge consultation with the cardio-renal division of FDA and, possibly with FDA's advisory committee to accomplish this task.